DESCRIPTION (adapted from the application) Polycystic kidney disease (PKD) is characterized by the progressive expansion of multiple cystic lesions, which compromise the function of normal parenchyma. Throughout the course of this disease, aspects of renal epithelial polarity, structure, and function are altered, changing the tubular microenvironment and ultimately causing the formation and progressive expansion of cystic lesions. While the human gene for autosomal recessive PKD (ARPKD) has not been cloned, the gene associated with the Oak Ridge polycystic kidney (orpk) mouse mutation has provided molecular insights into ARPKD. Further genetic analysis of the orpk disease gene, Tg737, has uncovered a critical role for its gene product during early embryogenesis. Unlike the orpk allele, where all homozygotes survive to birth, embryos homozygous for the Tg737-delta2-3-betaGal mutation arrest in development at mid-gestation and exhibit neural tube defects, enlargement of the pericardial sac and, most notably, left-right asymmetry defects. At mid-gestation the direction of heart looping is randomized, and at earlier stages in development lefty-2 and nodal, which are normally expressed asymmetrically, exhibit symmetrical expression in the mutant embryos. Expression of both Shh and Hnf3beta is down regulated in the midline (floorplate and notochord) at E8.0, indicating that there are significant alterations in midline development in mutants. Additionally, the ventral node cells in mutant embryos fail to express an apical central cilium, which is a characteristic and potentially functional feature of these cells. We propose that loss of Tg737 function in the early embryo causes abnormal or incomplete differentiation of the ventral node epithelium which alters the ability of these cells to properly differentiate as they migrate out of the node and contribute to developing midline structures. A defective midline then causes downstream developmental defects in left-right asymmetry and neural tube development leading to cardiac insufficiency and mid-gestational lethality. The failure of these polarized epithelial cells to properly differentiate in the ventral node of Tg737-delta2-3-betaGal homozygous embryos parallels the abnormal polarity of the EGFR and clonal expansion of principal cells in collecting tubule cysts of the orpk mouse model of ARPKD and in human ADPKD. Analysis of the fundamental cellular defects in ventral node epithelium and their subsequent effects on differentiation and development provides a novel system for investigating the function of the murine ARPKD disease gene Tg737. Knowledge gained from these studies will further our basic understanding and provide novel insight into the fundamental cellular defects in renal tubular epithelium associated with PKD.